Tuberculosis (TB) is an infectious disease of paramount public health importance. TB is increasingly difficult to control due to the HIV syndemic and escalating resistance to antibiotics. The key aspects of TB pathogenesis include intracellular parasitism of the causative agent Mycobacterium tuberculosis (Mtb) and a pernicious balance between insidious, asymptomatic infection and progression to active disease. We have discovered that the process called autophagy can kill intracellular Mtb. At the time we reported this newly-found power of cells to rid themselves of intracellular microbes, autophagy was not viewed as an immunological process, but rather as a cytoplasmic quality control and nutritional pathway. Today, based on our work and work by others, autophagy is perceived as a general antibacterial and antiviral mechanism, with control of Mtb being one of the leading examples. Our latest findings show that autophagy also acts as a suppressor of excessive immune responses that can cause inflammatory pathology and uncontrolled tissue damage. We need to answer two principal questions before we can effectively harness the power of autophagy for treatment and prevention of TB. We need to define the molecular machinery that captures intracellular Mtb and delivers it for degradation in autophagic organelles. Furthermore, we need to know if and how autophagy prevents immune responses that may cause pathology and progression to active disease. This proposal will close these gaps in our knowledge. The following are the specific aims of this proposal: Specific Aim 1. Define the cell-autonomous mechanism of autophagic elimination of Mtb. We will identify the autophagic pattern recognition receptors that recognize Mtb and deliver it to autophagosomes. We will test the hypothesis that IRGM, a genetic risk factor for TB and an enigmatic autophagy regulator, functions as a receptor recognizing the bacteria and orchestrates autophagy of Mtb. Furthermore, we will test a hypothesis that HIV co-infection influences the anti-Mtb action of IRGM. Specific Aim 2. Delineate the role of autophagy in preventing endogenous inflammation and pathogenic cytokine responses during Mtb infection. We will test the hypothesis that autophagy inhibits progression to active disease by preventing excessive inflammation and tissue damage.